Themis (for Thymocyte expressed molecule involved in selection) is a recently- discovered gene and protein that is highly expressed in immature thymocytes, and is also expressed at a lower level in mature T cells. It is a member of a small gene family of unknown function. Themis-deficient mice become obese and develop glucose intolerance and increased serum insulin, suggesting a relationship between Themis expression and prevention of the inflammation of adipose tissue that leads to metabolic syndrome and type II diabetes (T2D). T cells have recently been shown to be important in this process. Moreover, Themis was identified by genomics as showing a causal relationship to serum insulin level, with a protective effect against T2D. This proposal will investigate how expression of Themis in T cells of different lineages affects T cell involvement in adipose inflammation in response to obesity, and the metabolic syndrome that precedes T2D. It will test how the metabolic syndrome and development of T2D is exacerbated by loss of Themis, and the mechanism of action and specific T cell subsets involved. PUBLIC HEALTH RELEVANCE: The epidemic of obesity and Type II diabetes are becoming extremely important factors to the public health of the US and other developed nations. This project aims to understand the role of T cells in the initiation of the metabolic syndrome that leads to type II diabetes using a new mouse model.